I interviewed Dr. Snyder in June at his laboratory after learning that he received the 2005 Medal of Science from President Bush. Before our meeting I asked for a tour of his lab, where I was greeted by many of the happiest and most energetic investigators and staff I’ve seen anywhere. I was enchanted to hear their enthusiastic descriptions of their work and their fondness of Dr Snyder. I’ve heard similar remarks from colleagues who trained with him and later went on to outstanding careers of their own. This atmosphere, an obvious product of his personality, must contribute a lot to the exceptional scientific productivity of the laboratory.

I began by asking Dr. Snyder to describe his “advances that opened up the modern field of treatment of neuropsychiatric diseases”. With only a moment’s hesitation to organize his thoughts, he delivered a detailed and elegant account of years of complex neurobiological research, taking pains to credit each of his students for their contributions. It was a singular demonstration of his ability to communicate. Additional discussion of his current work took place by email.

It is impossible to describe all of his achievements in anything shorter than a volume. This report will focus on some of the ongoing work in his laboratory. The full text of Dr. Snyder’s summary of his work can be seen on the Internet at http://www.letreb.com/solomon_snyder_wins_prestigious_.htm

Glutamate is the major excitatory neurotransmitter in the brain and acts via several receptors, of which the NMDA subtype is best known.  Psychotomimetic drugs such as PCP act by blocking NMDA receptors and elicit a psychosis which resembles schizophrenia more than any other drug psychosis.  Administration to schizophrenics of D-serine in itself as well as related agents alleviates schizophrenic symptoms.  The French neuroscientist Phillipe Ascher discovered some years ago that the NMDA receptor must be activated by two agents and showed that glycine can work together with glutamate to activate the receptor.  Excess activation of NMDA receptors leads to neurotoxicity and stroke so that Ascher reasoned that the requirement of two neurotransmitters for one receptor (something which is unprecedented) functions as a safety mechanism – two keys for the lock – so that one might not get a stroke from eating a steak dinner.  However, glycine, like glutamate, is an abundant dietary constituent.  D-serine is the unnatural isomer whose existence in biology was discovered accidentally some years ago with D-serine occurring in the brain and virtually no other D-amino acid existing in all mammalian biology.  In fundamental studies of NMDA receptors, it was already known that D-serine was substantially more active than glycine, but at that time no one knew that D-serine even exists in biology. We have established that D-serine is the primary endogenous stimulus to the NMDA receptor, working together with glutamate. One direct item of evidence involved utilizing D-amino acid oxidase, an enzyme discovered by Hans Krebs in 1935 and long neglected as a meaningless protein since there were no D-amino acids in mammals.  We showed that, under physiologic conditions, D-amino acid oxidase is extremely selective for D-serine.  We used it to selectively degrade D-serine and show that NMDA neurotransmission was abolished even though glycine levels were completely normal.  We discovered an enzyme, serine racemase, which converts L-serine to D-serine.  We are currently examining mice with targeted deletion of serine racemase.  Hopefully, characterization of the behavior of these gene knockout mice will provide insights into the normal functions of D-serine.  This work is being carried out by Paul Kim, PhD. Paul is now a Hopkins Medical Student. Asif Mustafa, a MD, PhD, is now working on the project.

 We continue to work on gasses as neurotransmitters with much evidence for nitric oxide and carbon monoxide as signaling molecules.  Very recently, we have evidence that hydrogen sulfide (H2S) the foul smelling rotten egg odorant is a neurotransmitter.  Our collaborator, Dr. Rui Wang, created mice with a knockout of the gene for cystathione-gamma-lyase, the enzyme which we suspected might physiologically generate H2S from the amino acid cysteine.  We have shown that H2S formation is virtually abolished in lyase knockout mice.  Moreover, neurotransmission in the intestine, which underlies the relaxation phase of peristalsis, is substantially reduced in the knockout mice, indicating that H2S is a neurotransmitter of this process.  Interestingly, formerly we showed that nitric oxide and carbon monoxide are also neurotransmitters mediating peristalsis.  Our next challenge will be to work out the function for H2S neurotransmission in the brain by mapping the H2S neurons as well as by evaluating the behavior of the gene knockout mice.  Crystal Watkins, a MD, PhD student who is starting a psychiatry residency at Hopkins, did this work.

We are studying mechanisms of cell death and cell protection.  Bilirubin, long thought to be a toxic breakdown product of heme, appears to be a major cellular protectant.  This explains the paradox that bilirubin exists at all.  If one wanted to get rid of heme, the enzyme heme oxygenase breaks open the heme ring to generate the green pigment biliverdin, which can be excreted in the bile.  Surprisingly, biliverdin reductase then reduces biliverdin to the very insoluble bilirubin, which then must be conjugated to glucuronide for excretion.  Why?  It is well known that accumulation of bilirubin in the brain is neurotoxic.  Why would nature make bilirubin, which puts so large a portion of newborn babies at risk for kernicterus?  We found that bilirubin very potently prevents neurotoxicity by acting as an endogenous antioxidant.  However, because bilirubin is toxic, the body cannot produce large amounts of it despite the need to combat high concentrations of oxygen free radicals.  Instead, an ingenious cycle regenerates bilirubin.  Thus, whenever a molecule of bilirubin acts as an antioxidant, it itself is oxidized back to biliverdin, which is immediately converted by biliverdin reductase back to bilirubin.  When we made these findings, we then explored the clinical literature and discovered protective effects of bilirubin that had not been appreciated because they didn’t make sense. Individuals with Gilbert’s Syndrome, who are less capable of inactivating bilirubin and have moderately elevated levels, have only 1/5^th the incidence of cardiovascular disease of matched controls.  In other studies screening large populations, individuals with higher bilirubin levels have a higher incidence of cancer or heart disease.  This work is being carried out by Tom Sedlak, an MD, PhD psychiatrist doing postdoctoral training in our lab. 

You asked about my involvement with patients.  I wanted to be a psychiatrist long before I had any interest in research.  Indeed, I decided to be a psychiatrist while in high school and never wavered.  I enjoyed dynamically oriented psychotherapy and, according to my supervisors, was pretty darned good. For many years I continued taking time out of my other activities to see patients a few hours a week.

You asked about connections between my clinical psychiatric experience and what I did in the laboratory.  Once we identified opiate receptors, we were able to transfer this technology to studies of neurotransmitter receptors and focus with particular emphasis on dopamine receptors in order to address directly if neuroleptics might act by blocking dopamine receptors.  Because of my clinical background, I was aware of critical questions dealing with side effects of neuroleptics, such as extrapyramidal actions, which we showed to be correlated inversely with anticholinergic effects.  The ability to quantify potencies of both therapeutic and adverse effects of drugs at various neurotransmitter receptors monitored by ligand binding led to a new way of drug development in the pharmaceutical industry.

You asked how advances in neurobiology will shape clinical psychiatry.  The most direct and important impact will probably be in identifying genetic propensities for the major illnesses, schizophrenia and bipolar disorder.  Already, one gene has been directly implicated in a small group of patients with familial schizophrenia.  This gene, DISC1, has been shown by my colleague in the psychiatry and neuroscience departments, Dr. Akira Sawa, to regulate early brain development fitting with abundant evidence that schizophrenia is primarily a developmental rather than a neurodegenerative disorder.  Once we find genes that mediate psychiatric disturbance, it might be possible to develop novel and more selective therapies. 

In the context of my own musical background you ask about the potential influence of music upon scientific research.  I have long been impressed with the link between artistic creativity and scientific discovery.  Writing a song, drawing a picture, producing a poem all involve thinking new thoughts.  The more these thoughts are “out of the box,” the greater the creative advance.  Similarly, the more novel a scientific concept, the greater chance that it represents a major step forward.  In my own case, I love to write new songs – especially for my grandchildren – original melodies as well as words.  Similarly, in going over scientific projects with my students, I become impatient with dry analysis, in depth, of experimental details.  What really turns me on is coming up with a totally novel conceptualization that can clarify seemingly contradictory findings and provide insight into some important question.

Born in 1938 in Washington, DC, Dr Snyder worked at NIH in the laboratory of Seymour Kety while he was still in high school. He later worked with Julius Axelrod, who was awarded the Nobel Prize in 1970. A graduate of Georgetown School of Medicine, Snyder spent several more years working with Axelrod at NIH before starting a psychiatric residency at Hopkins in 1965. He became a full professor by l970 and in l980 he became Distinguished Service Professor of Neuroscience, Pharmacology and Psychiatry and Director of the Department of Neuroscience. He gained fame in 1972 with the discovery of opiate receptors in the brain. Over 150 of his former students occupy important scientific positions throughout the world.

Regarding his personal life, Dr Snyder said: “My wife, Elaine and I have three grandchildren, Abigail 8, Emily 6, and Leo 3.   The grandchildren are from our older daughter Judy, a psychiatrist in Philadelphia.  Our younger daughter Debbie is a screenwriter in Manhattan, unattached.  I do play the classical guitar and seriously considered a concert career, having performed publicly a good bit while a high school student.  Elaine completed the JHMI Mental Health Counselor program many years ago and is now retired after a productive career.”

Reference (1) http://www.acnp.org/Bulletin_March_Web_2005.htm